Similar to growing number of mental, developmental, and neurodegenerative disorders, spinocerebellar ataxia type 1 (SCA1) is caused by an expansion of a trinucleotide repeat in the SCA1 gene. The long-term objective of the proposed research is to understand the molecular mechanisms underlying neuronal dysfunction in SCA1. The mutation confers a novel function onto ataxin-1, the SCA1 gene product, but the exact nature of this function is unknown. The mutant protein forms nuclear inclusions in affected neurons and the molecular chaperone HDJ-2, ubiquitin, ant the proteasome all colocalize with ataxin-1 in these inclusions. Furthermore. Purkinje cell degeneration is worse in an SCA1 mouse model in the absence of the ubiquitin-protein ligase gene Ube3A. These findings led to the hypotheses that protein misfolding and\or the proteolytic system may be involved in neuronal dysfunction. This proposal aims at testing this hypothesis using two model systems for SCA1 pathology. First, a tetracycline-inducilble cell line will be used to determine the role of protein misfolding in aggregate formation, the turnover rate of mutant ataxin-1, and the effect of the mutant protein on the proteasome. Second, transgenic mice overexpressing Ube3a in Purkinje cells will be generated and mated with SCA1 transgenic mice to determine if enhancing the activity of one component of the ubiquitin-mediated proteolytic system is sufficient to suppress neuronal dysfunction. These studies will aid in understanding the mechanisms underlying neuronal dysfunction, not only in SCA1, but in an expanding group of neurological diseases and mental disorders.